Paired-associate Learning Task Research Articles

Assessing periadolescent memory ability and characterizing the development of a functional brain network vulnerable to Alzheimer’s disease

AbstractBackgroundIn typically presenting Alzheimer’s disease (AD), pathological changes to the hippocampus (Hc) and its associated functional brain networks result in impaired declarative/relational memory. While it is known that risk factors for AD (genetic, environmental, etc.) can impact hippocampal resting‐state functional connectivity (RSFC) later in life, the development of the hippocampus and its connections to other brain regions may also be influenced by such risk factors. The goal the current study was to characterize the neurodevelopmental changes in this hippocampal network during the periadolescent epoch and determine whether the observed changes were associated with declarative/relational memory ability. Therefore, we utilized a cross‐sectional approach to test whether individual differences in hippocampal RSFC covary with outcomes on a test of relational memory ability in periadolescent children.MethodData were drawn from an ongoing NIA‐funded project: the Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study. Our analysis was carried out using data from healthy periadolescent participants (N=90; age 8‐13 years). We assessed declarative/relational memory with Cambridge Cognition’s Paired Associates Learning (PAL) task. To conduct the resting‐state functional MRI analyses, we used a seed‐based approach with the bilateral hippocampus as the seed region of interest. We then analyzed the hippocampal RSFC data to and assessed covariance of individual patterns of hippocampal RSFC with memory performance measured with the PAL task.ResultOur preliminary findings, largely consistent with previous work, demonstrate patterns of hippocampal RSFC sharing territory with the ventral and lateral portions of the default mode network (DMN). In addition, we observed evidence of regional covariance between hippocampal RSFC and PAL task performance.ConclusionThe preliminary findings of the ongoing PRANK study indicate that hippocampal RSFC covaries regionally with hippocampal‐dependent memory ability in periadolescent children. Future work from the PRANK study aims to understand whether genetic and polygenic risk factors for AD influence this hippocampal network development. To do so, we will utilize participants’ AD polygenic risk scores, and determine whether those scores are related to individual differences in hippocampal RSFC.

Stop and think: Additional time supports monitoring processes in young children.

When children evaluate their certainty, monitoring is often inaccurate. Even though young children struggle to estimate their confidence, existing research shows that monitoring skills are developing earlier than expected. Using a paired associates learning task with integrated monitoring, we implemented a time window to-"Stop and Think"-before children generated their answers and evaluated their confidence in the chosen response. Results show that kindergarten and second grade children in the-"Stop and Think"-condition have higher monitoring accuracy than the control group. Implementing a time window thus seems to support children in their evaluation of different certainty levels. Relating individual differences in independently measured inhibitory control skills revealed a correlation between monitoring and inhibition for kindergarteners.

Paired associates learning is disrupted after unilateral parietal lobe controlled cortical impact in rats: A trial-by-trial behavioral analysis

Approximately 60–70 million people suffer from traumatic brain injury (TBI) each year. Animal models continue to be paramount in understanding mechanisms of cellular dysfunction and testing new treatments for TBI. Enhancing the translational potential of novel interventions therefore necessitates testing pre-clinical intervention strategies with clinically relevant cognitive assays. This study used a unilateral parietal lobe controlled cortical impact (CCI) model of TBI and tested rats on a touchscreen-based Paired Associates Learning (PAL) task, which is part of the Cambridge Neuropsychological Test Automated Battery. In humans, the PAL task has been used to assess cognitive deficits in the ability to form stimulus-location associations in a multitude of disease states, including TBI. Although the use of PAL in animal models could be important for understanding the clinical severity of cognitive impairment post-injury and throughout intervention, to date, the extent to which a rat model of TBI produces deficits in PAL task performance has not yet been reported. This study details the behavioral consequences of the CCI injury model with a Trial-by-Trial analysis of PAL performance that enables behavioral strategy use to be inferred. Following behavior, the extent of the injury was quantified with histology and staining for the presence of glial fibrillary acid protein and ionized calcium-binding adapter molecule 1. Rats that received unilateral CCI were impaired on the PAL task and showed more aberrant response-driven behavior. The magnitude of PAL impairment was also correlated with Iba1 staining in the thalamus. These observations suggest that PAL could be useful for pre-clinical assessments of novel interventions for treating TBI.

Effects of a brief afternoon nap on declarative and procedural memory

The relationship between sleep and memory consolidation has not been fully revealed. The current study aimed to investigate how a brief afternoon nap contributed to the consolidation of declarative and procedural memory by exploring the relationship between sleep characteristics (i.e., the durations of sleep stages and slow oscillation, slow-wave activity, and spindle activity extracted from sleep) and task performance and the relationship between delta, theta, alpha, and beta bands extracted from wake during task performance and task performance. Twenty-three healthy young adults underwent a paired associates learning task and a sequential finger-tapping task with easy and difficult levels and were tested for memory performance before and after the intervention (i.e., an about 30-min nap or stay awake). Electroencephalogram (EEG) signals were continously recorded during the whole experiment. Results revealed that a short afternoon nap improved movement speed for the procedural memory task, regardless of the task difficulty, but unaffected the performance on the declarative memory task. Besides, the improvement in movement speed for the easy procedural memory task was positively correlated with slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep but negatively correlated with slow oscillation and spindle activity during sleep stage 2 and NREM sleep, and the improvement in the difficult procedural memory task correlated positively with SWA during NREM sleep. Moreover, performance on the easy declarative and procedural memory tasks was negatively correlated with the relative power of alpha or theta; whereas the alpha band was positively correlated with the difficult declarative memory performance. These findings suggested that a brief afternoon nap with NREM sleep would benefit procedural memory consolidation but not declarative memory; such contribution of napping to memory consolidation would be either explained by the sleep characteristics or physiological arousal during performing tasks; task difficulty would moderate the relationship between the declarative memory performance and EEGs during task performance.

1312-P: Impaired Beta-Cell Function in Older Patients Corresponds to Changes in Salience Network Connectivity

The salience network (anterior cingulate cortex (ACC) —insula) plays an important role in regulating attention and memory in the context of decision making and has also been shown to be highly responsive to changes in peripheral glucose levels. Increased age is also associated with changes in glucose homeostasis and the salience network. To investigate these relationships, 40 healthy, cognitively normal, non-diabetic subjects (20 Young (age mean 28±1 years, BMI 28.1 ±1.1 kg/m2, HbA1c 5.3±0.1%) and 20 Old (age mean of 73±2 years, BMI 26.9±0.9 kg/m2, HbA1c 5.5±0.1%)) underwent an OGTT, resting state functional connectivity (FC) MRI brain scanning, and cognitive assessments (Cambridge Neuropsychological Test Automated Battery) . Despite similar BMI, HbA1C, and fasting glucose levels, older individuals had lower disposition index (young: 9±2, old: 3.3±0.4, p=0.005) indicating impaired β-cell function. There were no differences in measures of insulin sensitivity (HOMA-IR (p=0.38) or Matsuda index (p=0.70) . A seed-based analysis using a predefined cubic voxel in the ACC showed differences in FC between the ACC and the left insula (Main Effect by group, P<0.001) with lower connectivity values in Old compared to Young subjects. This connectivity value also correlated with errors on the Paired Associate Learning task, which tests attention and memory (r=-0.5, P=0.001) . Moreover, the connectivity values correlated with the disposition index in older subjects (r=0.49, P=0.03) but not younger subjects (P=0.9) . Thus, in our cohort of healthy, cognitively normal older subjects, impairments in beta-cell function are associated with altered functional connectivity within the salience network. These findings highlight the need for future investigations to determine whether mild age-related changes in glycemic control contribute to neurocognitive changes in older patients. Disclosure J.Deajon-jackson: None. C.Lacadie: None. C.Watt: None. D.Scheinost: None. J.J.Hwang: None. Funding Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342)

Neurobehavioral mechanisms underlying the effects of physical exercise break on episodic memory during prolonged sitting

Background and objectiveEpisodic memory is the ability that enables individuals to recall and re-experience previous events and usually includes information concerning the spatial and temporal context. This study examined the effects of a physical exercise break during a period of prolonged sitting on episodic memory. Furthermore, we aimed to investigate whether alterations of functional connectivity patterns might contribute to the exercise-induced changes in episodic memory. MethodsSixty healthy male college students were randomly assigned (1:1 ratio) to a prolonged-sitting group (PS group) or a physical-exercise-break group (PE group). The face-name paired-associate learning task was used to probe episodic memory. During the task, cortical hemodynamics in the prefrontal cortex were recorded using functional near-infrared spectroscopy (fNIRS). Changes in cortical hemodynamics were used to determine functional connectivity using graph-theoretical network analysis. ResultsThere was no between-group difference in neurobehavioral outcomes at the pretest assessment. During the posttest assessment, compared with the PS group, higher nodal efficiency in the anterior prefrontal cortex (orbitofrontal and frontopolar cortices) was observed during the encoding phase (FDR corrected p values = 0.039), and higher nodal efficiency and degree centrality of orbitofrontal cortex were observed in the retrieval phase in the PE group (FDR corrected p values = 0.035). Moreover, the PE group showed closer temporal correlational interactions between the dorsolateral prefrontal cortex and the anterior prefrontal cortex in the left hemisphere during the episodic memory encoding phase (FDR corrected p values = 0.043), when compared to the PS group. Neither significant between-group difference in accuracy nor correlations between neural and behavioral outcomes were observed after the intervention. ConclusionOur findings suggest that a physical exercise break during a prolonged sitting period has neither a beneficial nor a detrimental effect on behavioral performance concerning episodic memory. However, physical breaks do facilitate functional connectivity patterns of the prefrontal cortex while performing a episodic memory task.

Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory.

Cognitive impairment is a common symptom after traumatic brain injury (TBI). Memory, in particular, is often disrupted during chronic post-injury recovery. To understand the sex-specific effects of brain injury on retrograde and anterograde memory, we examined paired associate learning (PAL), spatial learning and memory, and fear memory after lateral fluid percussion TBI. We hypothesized that male and female mice would display unique memory deficits after TBI. PAL task acquisition was initiated via touchscreen operant conditioning 22 weeks before sham injury or TBI. Post-injury PAL testing occurred 7 weeks post-injury. Barnes maze and fear conditioning were completed at 14- and 15-weeks post-injury, respectively. Contrary to our expectations, behavioral outcomes were not primarily influenced by TBI. Instead, sex-specific differences were observed in all tasks which exposed task-specific trends in male TBI mice. Male mice took longer to complete the PAL task, but this was not affected by TBI and did not compromise the ability to make a correct choice. Latency to reach the goal box decreased across testing days in Barnes maze, but male TBI mice lagged in improvement compared to all other groups. Use of two learning indices revealed that male TBI mice were deficient in transferring information from 1 day to the next. Finally, acquisition and contextual retention of fear memory were similar between all groups. Cued retention of the tone-shock pairing was influenced by both injury and sex. Male sham mice displayed the strongest cued retention of fear memory, evidenced by increased freezing behavior across the test trial. In contrast, male TBI mice displayed reduced freezing behavior with repetitive tone exposure. An inverse relationship in freezing behavior to tone exposure was detected between female sham and TBI mice, although the difference was not as striking. Together, these studies show that retrograde memory is intact after lateral TBI. However, male mice are more vulnerable to post-injury anterograde memory deficits. These behaviors were not associated with gross pathological change near the site injury or in subcortical brain regions associated with memory formation. Future studies that incorporate pre- and post-injury behavioral analysis will be integral in defining sex-specific memory impairment after TBI.

Measuring the developmental relationship between memory ability and organization of a functional brain network vulnerable to Alzheimer’s disease: Preliminary findings from the PRANK study

AbstractBackgroundThe hallmark memory impairments of typically presenting Alzheimer’s disease (AD) are associated with pathological changes of the hippocampus. While it is known that the hippocampus is necessary for normal relational memory performance, the development of functional brain networks associated with the hippocampus is not well characterized, particularly in the periadolescent epoch. The development of the hippocampus and its associated functional brain network may be influenced by genetic, environmental, or other risk factors for AD, potentially creating vulnerabilities to AD in later life. This project explores the neurodevelopment of this hippocampal network to determine how individual differences in functional connectivity impact relational memory abilities during the periadolescent epoch. Here, we utilized preliminary data from the NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study, which aims to improve insight regarding how brain and cognitive development is affected by polygenic risk for Alzheimer’s disease. Our continuing study is recruiting healthy periadolescent individuals (8‐13 years of age). Here we report preliminary cross‐sectional findings from the PRANK study exploring how individual differences in hippocampal resting‐state functional connectivity (RSFC) covary with declarative/relational memory ability.MethodAnalyses were conducted on preliminary data from healthy periadolescent participants (n=40). Declarative/relational memory performance was measured with Cambridge Cognition’s Paired Associates Learning (PAL) task. Resting‐state functional MRI data was analyzed using a seed‐based approach with the bilateral hippocampus as the seed region of interest. RSFC data were analyzed to determine their covariance with relational memory ability (operationalized as PAL performance).ResultOur analysis revealed patterns of hippocampal RSFC that were broadly consistent with prior work, sharing the territory of the default mode network (DMN). We also observed regional covariance between hippocampal RSFC and performance on the PAL task.ConclusionThe present work describes preliminary findings of the ongoing PRANK study. Our preliminary observations are consistent with the perspective that hippocampal RSFC covaries with hippocampal‐dependent declarative/relation memory ability among periadolescent children. To understand whether this hippocampal network development is susceptible to genetic risk factors for AD, future work from the PRANK study will utilize participants’ AD polygenic risk scores to determine whether those scores are related to individual differences of hippocampal RSFC.

Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach

Several observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.

Computerized paired associate learning performance and imaging biomarkers in older adults without dementia.

This cross-sectional study examined whether performance on the computerized Paired Associate Learning (PAL) task from the Cambridge Neuropsychological Test Automated Battery is associated with amyloid positivity as measured by Positron Emission Tomography, regional volume composites as measured by Magnetic Resonance Imaging, and cognitive impairment. Participants from the BIOCARD Study (N = 73, including 62 cognitively normal and 11 with mild cognitive impairment; M age = 70years) completed the PAL task, a comprehensive clinical and neuropsychological assessment, and neuroimaging as part of their annual study visit. In linear regressions covarying age, sex, years of education and diagnosis, higher PAL error scores were associated with amyloid positivity but not with medial temporal or cortical volume composites. By comparison, standard neuropsychological measures of episodic memory and global cognition were unrelated to amyloid positivity, but better performance on the verbal episodic memory measures was associated with larger cortical volume composites. Participants with mild cognitive impairment demonstrated worse cognitive performance on all of the cognitive measures, including the PAL task. These findings suggest that this computerized visual paired associate learning task may be more sensitive to amyloid positivity than standard neuropsychological tests, and may therefore be a promising tool for detecting amyloid positivity in non-demented participants.

Age-related impairments on the touchscreen paired associates learning (PAL) task in male rats

Discovery research in rodent models of cognitive aging is instrumental for identifying mechanisms of behavioral decline in old age that can be therapeutically targeted. Clinically relevant behavioral paradigms, however, have not been widely employed in aged rats. The current study aimed to bridge this translational gap by testing cognition in a cross-species touchscreen-based platform known as paired-associates learning (PAL) and then utilizing a trial-by-trial behavioral analysis approach. This study found age-related deficits in PAL task acquisition in male rats. Furthermore, trial-by-trial analyses and testing rats on a novel interference version of PAL suggested that age-related impairments were not due to differences in vulnerability to an irrelevant distractor, motivation, or to forgetting. Rather, impairment appeared to arise from vulnerability to accumulating, proactive interference, with aged animals performing worse than younger rats in later trial blocks within a single testing session. The detailed behavioral analysis employed in this study provides new insights into the etiology of age-associated cognitive deficits.

What I know and what you know: The role of metacognitive strategies in preschoolers’ selective social learning

The mechanisms which guide selective learning in young children have been a source of debate. Two experiments were conducted to identify which cognitive processes are involved in selective social learning in preschoolers. In experiment 1, we administered a paired-associate learning task, and collected accuracy and latency of explicit confidence judgments, measuring both implicit and explicit metacognitive monitoring. Results revealed that better implicit metacognitive monitoring predicted better performance on a selective learning task. In experiment 2, we obtained a parental report of children’s theory of mind skills (CSUS) and administered an information-seeking task, measuring implicit metacognitive control. Results revealed that both scores on the metacognitive control task and on the theory of mind questionnaire significantly predicted selective learning performance. These studies provide evidence of an association between preschoolers’ selective learning and implicit metacognitive strategies, but also suggest that explicit metacognitive learning strategies may guide selective learning later in development.

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a pilot investigation.

Outcome processing, the ability to learn from feedback, is an important component of adaptive behavior and rehabilitation. Evidence from healthy adults implicates the striatum and dopamine in outcome processing. Animal research shows that damage to dopaminergic pathways in the brain can lead to a disruption of dopamine tone and transmission. Such evidence thus suggests that persons with TBI experience deficits in outcome processing. However, no research has directly investigated outcome processing and associated neural mechanisms in TBI. Here, we examine outcome processing in individuals with TBI during learning. Given that TBI negatively impacts striatal and dopaminergic systems, we hypothesize that individuals with TBI exhibit deficits in learning from outcomes. To test this hypothesis, individuals with moderate-to-severe TBI and healthy adults were presented with a declarative paired-associate word learning task. Outcomes indicating performance accuracy were presented immediately during task performance and in the form of either monetary or performance-based feedback. Two types of feedback provided the opportunity to test whether extrinsic and intrinsic motivational aspects of outcome presentation play a role during learning and outcome processing. Our results show that individuals with TBI exhibited impaired learning from feedback compared to healthy participants. Additionally, individuals with TBI exhibited increased activation in the striatum during outcome processing. The results of this study suggest that outcome processing and learning from immediate outcomes is impaired in individuals with TBI and might be related to inefficient use of neural resources during task performance as reflected by increased activation of the striatum.

Effects of a novel M4 muscarinic positive allosteric modulator on behavior and cognitive deficits relevant to Alzheimer's disease and schizophrenia in rhesus monkey

Alzheimer's disease (AD) is a profoundly debilitating neurodegenerative disorder characterized most notably by progressive cognitive decline, but also agitation and behavioral disturbances that are extremely disruptive to patient and caregiver. Current pharmacological treatments for these symptoms have limited efficacy and significant side effects. We have recently reported the discovery of Compound 24, an M4 positive allosteric modulator (PAM) that is potent, highly selective, and devoid of cholinergic-like side effects in rats. In order to further evaluate the translatability of the effects of compound 24 in primates, here we describe the effect of Compound 24 on three behavioral and cognition assays in rhesus monkeys, the stimulant induced motor activity (SIMA) assay, the object retrieval detour task (ORD), and the visuo-spatial paired-associates learning (vsPAL) task. As far as we know, this is the first such characterization of an M4 PAM in non-human primate. Compound 24 and the clinical standard olanzapine attenuated amphetamine induced hyperactivity to a similar degree. In addition, Compound 24 demonstrated procognitive effects in scopolamine-impaired ORD and vsPAL, and these effects were of similar magnitude to donepezil. These findings suggest that M4 PAMs may be beneficial to diseases such as Alzheimer's disease and schizophrenia, which are marked by behavioral disturbances as well as deficits in cognitive function.

Hypnotic Suggestions Increase Slow-Wave Parameters but Decrease Slow-Wave Spindle Coupling.

PurposeSleep, in particular slow-wave sleep, is beneficial for memory consolidation. In two recent studies, a hypnotic suggestion to sleep more deeply increased the amount of slow-wave sleep in both a nap and a night design. In spite of these increases in slow-wave sleep, no beneficial effect on declarative memory consolidation was found. As coupling of slow-waves and sleep spindles is assumed to be critical for declarative memory consolidation during sleep, we hypothesized that the missing memory benefit after increased SWS could be related to a decrease in slow-wave/spindle coupling.Participants and MethodsData from 33 highly hypnotizable subjects were retrieved from a nap (n = 14) and a night (n = 19) study with a similar design and procedure. After an adaptation session, subjects slept in the sleep laboratory for two experimental sessions with polysomnography. Prior to sleep, a paired-associate learning task was conducted. Next, subjects either listened to a hypnotic suggestion to sleep more deeply or to a control text in a randomized order according to a within-subject design. After sleep, subjects performed the recall of the memory task. Here, we conducted a fine-grained analysis of the sleep data on slow-waves, spindles and their coupling.ResultsIn line with our hypothesis, listening to a hypnosis tape decreased the percentage of spindles coupled to slow-waves. Slow-wave parameters were consistently increased, but sleep spindles remained unaffected by the hypnotic suggestion.ConclusionOur results suggest that selectively enhancing slow-waves without affecting sleep spindles might not be sufficient to improve memory consolidation during sleep.

Partial mGlu5 Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without Affecting Cognition or Quantitative EEG.

Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor subtype 5 (mGlu5) demonstrate anxiolytic-like and antidepressant-like effects yet concern regarding adverse effect liability remains. Functional coupling of mGlu5 with ionotropic N-methyl-D-aspartate receptors (NMDARs) represents a potential mechanism through which full inhibition leads to adverse effects, as NMDAR inhibition can induce cognitive impairments and psychotomimetic-like effects. Recent development of “partial” mGlu5 NAMs, characterized by submaximal but saturable levels of blockade, may represent a novel development approach to broaden the therapeutic index of mGlu5 NAMs. This study compared the partial mGlu5 NAM, M-5MPEP, with the full mGlu5 NAM, VU0424238 on sleep, cognition, and brain function alone and in combination with a subthreshold dose of the NMDAR antagonist, MK-801, using a paired-associates learning (PAL) cognition task and electroencephalography (EEG) in rats. M-5MPEP and VU0424238 decreased rapid eye movement (REM) sleep and increased REM sleep latency, both putative biomarkers of antidepressant-like activity. Neither compound alone affected accuracy, but 30 mg/kg VU0424238 combined with MK-801 decreased accuracy on the PAL task. Using quantitative EEG, VU0424238, but not M-5MPEP, prolonged arousal-related elevations in high gamma power, and, in combination, VU0424238 potentiated effects of MK-801 on high gamma power. Together, these studies further support a functional interaction between mGlu5 and NMDARs that may correspond with cognitive impairments. Present data support further development of partial mGlu5 NAMs given their potentially broader therapeutic index than full mGlu5 NAMs and use of EEG as a translational biomarker to titrate doses aligning with therapeutic versus adverse effects.

Effective cognitive screening tools for Alzheimer's disease in the primary care setting: the role of the visual paired associative learning task.

Effective cognitive screening tools for Alzheimer's disease in the primary care setting: the role of the visual paired associative learning task.

T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment

A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer's disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative MRI measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n = 49) compared to healthy older controls (n = 99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships.

Differences in auditory associative memory between younger adults and older adults

ABSTRACT Aging impairs visual associative memories. Up to date, little is known about whether aging impairs auditory associative memories. Using the head-related-transfer function to induce perceived spatial locations of auditory phonemes, this study used an audiospatial paired-associates-learning (PAL) paradigm to assess the auditory associative memory for phoneme-location pairs in both younger and older adults. Both aging groups completed the PAL task with various levels of difficulty, which were defined by the number of items to be remembered. The results showed that compared with younger participants' performance, older participants passed fewer stages and had lower capacity of auditory associative memory. For maintaining a single audiospatial pair, no significant behavioral differences between the two aging grous werefound. However, when multiple sound-location pairs were required to be remembered, older adults made more errors and demonstrated a lower working memory capacity than younger adults. Our study indicates aging impairs audiospatial associative learning and memory.

Ocular measures during associative learning predict recall accuracy

The ability to form associations between stimuli and commit those associations to memory is a cornerstone of human cognition. Dopamine and noradrenaline are critical neuromodulators implicated in a range of cognitive functions, including learning and memory. Eye blink rate (EBR) and pupil diameter have been shown to index dopaminergic and noradrenergic activity. Here, we examined how these ocular measures relate to accuracy in a paired-associate learning task where participants (N = 73) learned consistent object-location associations over eight trials consisting of pre-trial fixation, encoding, delay, and retrieval epochs. In order to examine how within-subject changes and between-subject changes in ocular metrics related to accuracy, we mean centered individual metric values on each trial based on within-person and across-subject means for each epoch. Within-participant variation in EBR was positively related to accuracy in both encoding and delay epochs: faster EBR within the individual predicted better retrieval. Differences in EBR across participants was negatively related to accuracy in the encoding epoch and in early trials of the pre-trial fixation: faster EBR, relative to other subjects, predicted poorer retrieval. Visual scanning behavior in pre-trial fixation and delay epochs was also positively related to accuracy in early trials: more scanning predicted better retrieval. We found no relationship between pupil diameter and accuracy. These results provide novel evidence supporting the utility of ocular metrics in illuminating cognitive and neurobiological mechanisms of paired-associate learning.